Method for curing cyanoacrylate adhesives

ABSTRACT

A new adhesive method using an adhesive composition including cyanoacrylate adhesive and a stabilizing agent to join together portions of a substrate, particularly useful in suturing and similar medical procedures, is disclosed. It is based on the discovery that remarkable improvements are obtained by adding a step of removing stabilizing agent from such adhesive compositions in the manufacturing process with the prior known steps of (a) providing an adhesive composition including cyanoacrylate adhesive and a stabilizing agent, (b) presenting a substrate to receive at least a portion of such cyanoacrylate adhesive and (c) applying such portion to the substrate. Devices for use in performing the method are described.

CROSS REFERENCE TO RELATED APPLICATION

[0001] This application relates to U.S. patent application Ser. No.09/982,226, filed Oct. 19, 2001, which is currently pending.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] This invention relates broadly to a method of treating stabilizedcyanoacrylate adhesives prior to their application to a substrate,particularly with reference to medical procedures using such adhesives.

[0004] 2. Description of the Prior Art

[0005] Medical interest in cyanoacrylate polymers has been apparentsince at least the mid-nineteen sixties as evidenced by numerous reportson its use as a tissue bonding agent. Collins et al. reported on theeffectiveness of homologous chain cyanoacrylates for bonding ofbiological substrates. J. A. Collins, et al., ARCH. SURG. Vol. 93, 428September 1966; F. Leonard et al., J.A.P.S. Vol. 101617, 1966. Botharticles report the observation of high rates of polymerization withlonger chain esters than with the methyl or ethyl monomers. Thereappeared to be more biocompatability with the longer chains as noted bythe ease of spreading monomer films on bio-substrates. This contrastedwith in vitro polymerizations where the lower homologues reacted muchfaster. There was particular interest in the degradation of thesepolymers as they related to possible harmful effects that would precludetheir use in surgery.

[0006] Woodward et al. reported histotoxicity of these monomers in rattissue. S. C. Woodward, et al., ANN. SURG. Vol. 162, July 1965. Thestudy involved in situ polymerization of three cyanoacrylate monomers:methyl, hexyl, decyl. It was reported that histotoxic effects weregreatest with methyl and decreased with the other two monomers.

[0007] The same group reported on the use of radioactive methylcyanoacrylate for monitoring routes for the loss of the polymer. J. J.Cameron et al., SURGERY, Vol. 58, August 1965; C. H. McKeever, U.S. Pat.No. 2,912,454, Nov. 10, 1950. Results indicated that the polymer wasdegraded and excreted principally through the urine and feces. Analysisof the animal's organs revealed no signs of radioactivity. This impliedno degradation products were incorporated into any of the animal'smetabolic pathways. By analogy to poly-vinylidene cyanide, they notedthat the cyanoacrylate polymer degraded in the presence of water andmore so in the presence of bases. The first observed degradation productturned out to be one of the starting materials, i.e., formaldehyde. Invitro studies have shown that the polymers degrade via hydrolyticscission in homogeneous as well as heterogeneous conditions. F. Leonardet al., J.A.P.S., Vol. 10: 259, 1966. These degradation products wereconfirmed to be formaldehyde and the corresponding cyanoacetate. Theconditions of solution degradation affected the consequent rates,namely, under neutral conditions rates decreased as the homologousseries was ascended while alkaline conditions increased all rates.

[0008] The same study reported that the hydroxyl group was evident inthe polymer as the initiating species. This was concluded from infraredspectral data that displayed hydroxyl group absorption at 3600 cm(−1).Further support for this is the noted suppression of the OH as water isreplaced with methanol and the observed methoxy absorption at 1100cm(−1). Preferential initiation was shown to occur with NH₂ containingsubstances such as pyridine, cysteine, alanine, and glycine in aqueoussolutions. This suggested that in vivo adhesion was more than amechanical interlocking of the solid polymer with the tissue. Thisappears to be the case as it was noted that typical polymer solventswere not effective in solvating tissue-bound polymer. From this itappears that in vivo studies of degradation do not necessarilycorrespond to in vitro conditions. Part of the degradation mechanismrelies on the conditions of the polymer for hydrolytic scission. Thechemical bonding of the polymer excludes this surface from hydrolyticactivity. A mechanism of degradation was proposed that suggests anaction similar to unzipping in acrylics, however, the difference beingthat the monomer is not regenerated. The proposed mechanism necessitatesthe presence of the hydroxyl as well as the presence of water.

[0009] An unusual effect was reported regarding the aqueous degradationof isobutyl cyanoacrylate. R. H. Lehman et al., ARCH. SURG. Vol.93:441,1966. Of the monomers tested (methyl, propyl, butyl, isobutyl,heptyl, octyl), it was the only one that degraded more rapidly than anyof the unbranched homologues, with the exception of the methyl monomer.

[0010] A second study reported that in vivo experimentation givescredence to the chain scission mechanism by hydrolysis. M. Yonezawa etal., YUKI GOSEI KAGAKU KYOKAISHI, Vol. 25, 1967. When beta-(14) carbontagged cyanoacrylate is implanted in rats, radioactive urea is isolatedfrom urine. This suggests that tagged formaldehyde is released,converted to carbon dioxide and in turn reacts with ammonia to produceurea. F. Leonard, ADHES. BIOL. SYS. 1970.

[0011] Rates of degradation on ethyl, butyl, and hexyl cyanoacrylateswere evaluated with regards to molecular weights, concentrations, andside chain structures. W. R. Vezin et al., J. PHARM. PHARMACOL., Vol.30, 1978, Suppl. The method employed buffered systems of pH ranges from5.97 to 7.88. As expected, the rates increased with increasing pH.Scanning electron microscopy of the degraded polymer indicated thatreaction occurs at the surfaces and not internally through diffusion. Itwas postulated that the greater the length of the alkyl side chain, themore protection provided to the labile hydroxyl end of the polymerchain. This in turn would provide greater resistance to degradation ofthe polymer. Degradation rates do in fact correspond to chain lengthprotection. The relative rates of degradation for hexyl, butyl, andethyl were, respectively, 1.0, 1.36, 9.55.

[0012] The same group reported on a study whereby degradation rates wereretarded by increasing the chain length of the polymer. W. R. Vezin etal., J. BIOMED. MAT. RES., Vol. 93, 1980. Very small quantities ofimpurities in the monomers had a significant impact on the final outcomeof the degree of polymerization. Further to this study, within theethoxyethyl system, longer chain length enhanced the degradationresistance of the resultant polymer.

[0013] A comparative study of ethyl cyanoacrylate and polyurethanein-situ generated adhesives and coatings was reported in U.S. Pat. No.4,057,535 to Lipatova et al. The study claimed the superiority of thepolyurethane structure due to high flexibility and compatibility withthe treated tissues. The single comparison was made with incised tissueand consequent application between the wound edges. Inferiority of thisapplication for the cyanoacrylate was readily evident, but true topicalapplications were not compared. Of eleven examples given, four were of atopical method, yet no data was presented as no application of the ethylor any other homologue was done conjunctively for comparative efficacy.A further deficiency of this patent is the practicality of use. Noindication is given for a device to properly apply the two part systemand appears to indicate an at-site preparation.

[0014] Another patent, U.S. Pat. No. 5,192,536 to Robinson overcomes theissue of the apparent difficulties associated with the inventiondisclosed in U.S. Pat. No. 4,057,535 by taking preformed polyurethaneand dissolving it in a rapidly evaporating solvent such astetrahydrofuran. The composition is designed to form a “membrane-likecover over the wound” and “assists in maintaining closure of the wound”.Again no comparative studies were reported.

[0015] U.S. Pat. No. 3,995,641 to Kronauthal et al. discusses thenovelty of modified cyanoacrylates, namely, carbalkoxyalkylcyanoacrylates. The patent discloses their usefulness as a tissueadhesive in surgical applications. The presumed superiority of theseproducts was attributable to the rapid hydrolytic decay and concurrentlow degree of histotoxicity. Since no data is presented regardingformaldehyde evolution, it is presumed that the hydrolysis mechanismdoes not scission the polymer to generate it.

[0016] U.S. Pat. No. 5,254,132 to Bartley et al. discloses the use of ahybrid method of surgical application of cyanoacrylates. It discloses acombination of sutures and adhesive such as to be mutually isolated fromeach other, but to both support the re-growth of the tissue in the woundarea. The '132 patent addresses the issue of insuring no contact ofadhesive in the suture area so as to assure no inclusions of thecyanoacrylate. The disclosed method appears to be awkward andcumbersome, and requires a very effective and controlled dispensing ofthe adhesive without contacting the suture. Additional concern isindicated as a suggestion is made to employ a solvent (acetone) if anysurgical instrument happens to be bonded inadvertently to the treatedarea.

[0017] U.S. Pat. No. 5,328,687 to Leving et al. attacks the formaldehydeissue by incorporating a formaldehyde scavenger, such as, sodiumbisulfite. The various compositions were evaluated via in-vitroexperimentation. The examples presented all had a presumably excessivelevel of scavenger. The representative compositions had loadings of 20%of a scavenging agent that was designed to offset formaldehyde emissionsthat were at 0.1%. As indicated previously, in-vitro and in vivoconditions are not identical and certainly not in this instance. Thein-vitro conditions presented in the '687 patent do not factor in thedynamic conditions in living tissue. The surgically treated area wouldbe under continuous and changing fluids as the organ attempts to bringin the necessary biocomponents to heal the traumatized tissue. As such,it would not be expected that the scavenger/formaldehyde ratio would bemaintained as it was in the in-vitro state. It could be speculated thatthe use of such high loadings of any fluid solubilized additives wouldcontribute to greater formaldehyde emissions. This can be assumed to bea consequence of dissolution of the additives resulting in cavities inthe polymer, thereby promoting greater surface area for hydrolyticdegradation.

[0018] U.S. Pat. No. 5,403,591 to Tighe et al. relates to the use ofcyanoacrylates for treatment of skin irritations that progress toulcerations. It would be assumed that these conditions could beconsidered wound formations, e.g., see U.S. Pat. No. 3,995,641.

[0019] U.S. Pat. Nos. 5,928,611 to Leving, 5,981,621 to Clark et al.,6,099,807 to Leving, 6,217,603 to Clark et al. describe methods ofinducing cure of cyanoacrylates by passing the adhesive through a porousapplicator tip containing substances that initiate the polymerization.These substances co-elute and dissolve into the adhesive as it is forcedthrough the porous tip.

[0020] U.S. Pat. No. 6,143,352 to Clark et al. describes methods ofaltering the pH environment of cyanoacrylates in order to attenuate oraccelerate the rate of hydrolytic degradation by uses of acid andalkaline additives. The formulation of acidic modifiers is problematicas they tend to inhibit the primary characteristic of these materials,namely, rapid cure on application to tissue. Data is presented oneffects of acidic compositions on previously cured cyanoacrylates, noton in situ applied compositions.

[0021] All of these methods rely on the addition of various compositionsto affect the accelerated cure onto a desired substrate. Thesecompositions may induce polymerization by creating a greater number ofinitiation sites and or orientation of the monomer for more facilepolymerizations. Other plausible mechanisms can be evoked, but the factremains that the added materials become a part of the composition(undesirable for many medical applications). As such, these chemicalinclusions may elicit unfavorable reactions in the cured state. Inparticular, the use of pH-based accelerators may contribute to thealkaline hydrolysis of the cyanoacrylate polymer.

[0022] This is particularly undesirable in medical applications of thecyanoacrylates as the hydrolysis results in the evolution offormaldehyde. A certain level of formaldehyde can be tolerated by tissueas it is able to dispose of reasonable concentrations. A solutionproposed in the prior art has been increasing the chain length of thecyanoacrylate monomer side group; in particular, that it be alkyl so asto impart hydrophobic character to the resulting polymer.

[0023] The prior art methods and compositions have been able to achievea synthesis of the octyl cyanoacrylate at economic levels forapplications in the medical field, although improbable for uses incommercial applications due to reaction yields. A number of methods havebeen attempted to improve yields. Yin-Chaos Tseng et al., BIOMATERIALS,Vol 11, 1990. The variables looked at included: azeotropes, temperatureand formaldehyde/cyanoacetate ratio. Other methods have also includedassessment of different catalysts for the condensation reaction.Regardless of the methods tried, yields become increasingly smaller asthe cyanoacetate pendant group becomes larger.

[0024] An attempt to improve yields is reported in U.S. Pat. No.6,245,933 to Malofsky. This method attempts to avoid yield losses byproducing the high yield cyanoacrylate prepolymers of the lowerhomologues (methyl & ethyl) and then proceed through atransesterification with a longer chain alcohol such as the octyl. Threereported examples with 2-octanol gave yields ranging from 21.8% to 36.2%of crude monomer.

[0025] From this, it can be seen that high yields are difficult and nodoubt subsequent work-up to medically acceptable products result in evenlower product output. The difficulty with methods such as discussedabove, is the undesirable side products which are difficult to removefrom the main stream. In particular, it is difficult to achieve completetransesterification reactions on polymeric moieties because of stericobstruction. As a consequence, purity is compromised as the initialcyanoacrylate prepolymer is not completely reacted and the lowerhomologue co-distills with the desired product.

[0026] Other additives have been used to attenuate various properties,such as modulus (elasticity), viscosity, thermal resistance, etc. Eachand every additive becomes a substance that must be removed by thesurrounding tissue, which generally does not assist in recovery of thedamaged area. In that regard, the addition of these additives must weighthe effect of property improvements against the effect on tissuecompatibility.

[0027] In contrast to additives for the cured adhesives are additivesformulated into the synthesized monomers. The synthetic route formonomer production relies on two principal groups of stabilizers. Thefirst group is chosen from substances capable of preventing free radicalpolymerization and the second group inhibits the anionic polymerization.

[0028] The critical step in the production of these monomers relies onthe high temperature thermal degradation of the polymer generated fromthe formaldehyde-cyanoacetate reaction. These temperatures span therange of 150° C. to excesses of 200° C. Under ideal conditions, thispolymer will undergo a clean unzipping reaction that releases thecyanoacrylate monomer. This begins to take place in the lowertemperature regions and must be gradually elevated to extract theincreasingly difficult boiling off of the monomer. Elevation of thetemperature is necessary as byproducts form and increasingly hamper thevolatilization of the desired monomer.

[0029] In order to prevent the thermal reversal of the monomer back topolymer as it is generated and exits the body of fluid polymer in thereaction vessel, retarders or inhibitors are added at the beginning ofthis process. These substances react with free radicals to form a stableunreactive species, thereby halting the thermal polymerization typicalof vinyl monomers. Quinones are the most often used substances in thisgroup. Typical, but not exclusive, are hydroquinone and methyl etherhydroquinone. The presence of these additives is most critical in themonomer-polymer mix in the reaction vessel. Once the monomer isvaporized, it is quickly cooled to ambient conditions as it is distilledover to a suitable receiver.

[0030] The second group of stabilizers are used to prevent the anionicpolymerization of the monomer in the reaction vessel as well as thevapor and collected liquid monomer in the receiver. Those knowledgeablein the art are quite familiar with these substances. Typical, and again,not exclusive, are the sulfonic acids and sulfur dioxide. In general,acidic substances are chosen to effect stabilization not only during theproduction of these monomers but further for stabilization duringstorage.

[0031] A fine line exists in the levels of these anionic stabilizers. Ifthere is insufficient loading of these acids during the polymerunzipping to monomer, the vaporized and condensing monomer will begin torepolymerize throughout the system. On the other hand, if too muchanionic stabilizing takes place in the distilled monomer, the desiredrepolymerization is not easily accomplished. This is evidenced by thosepatents cited above that deal with the loading of alkaline substancesand other anion polymer promoting initiators in a porous tip. Theseadditives are necessary to overcome the excessive levels of anionicstabilizers that co-distill during the distillation of monomer.

[0032] In the manufacture of the lower homologues such as the methyl,ethyl, and butyl monomers, the degradation of the polymer to monomer ismuch more effective and gentle, requiring lower levels of these anionicstabilizers. The resultant distilled monomers are thereby stabilizedsufficiently and in some cases additional acid is charged, usually under100 parts per million, to effect a useful shelf life for commercialapplications.

[0033] These lower homologues are, as are all of the cyanocarylates(with some exceptions such as the difunctional ones), distilled undervacuum conditions. The typical vacuum is in the 0.5 mm Hg to 2.0 mm Hg.As the molecular weight of these monomers increases, the required vacuumconditions become more critical. In order to effectively distill thehigher molecular weights, the vacuum conditions must continue beyond therange of approximately 0.5 mm Hg. Higher distillation temperatures withpoor vacuum conditions results in increasing levels of undesirablebyproducts, and consequent poor yields and inferior product.

[0034] As a typical example, it is necessary to achieve a vacuum in therange of approximately 0.01 mm Hg to 0.05 mm Hg for the octyl monomerand higher homologues in order to effectively distill the monomers in anondestructive process. This, however, is the crux of the problem in theisolation of these monomers as confronted in the prior art methods andsystems.

[0035] The lower homologues and typical anionic stabilizers have asufficiently large difference in their respective boiling points, suchthat very little stabilizer is co-distilled with the monomer. This,however, becomes an increasingly important issue as the vacuum levelsproceed to better distill over the higher boiling monomers like theoctyl, decyl and so on. The consequence then is that increasing levelsof the stabilizer co-distill along with the desired monomer. Theresultant isolated monomer is excessively loaded with anionicstabilizer(s) thus requiring the devices referred to above.

[0036] In addition, and as generally discussed above, prior art methodsfor the synthesis of cyanoacrylate monomers generally require theaddition of acids and free radical inhibitors during the monomersynthesis. The free radical inhibitors prevent premature polymerizationduring the thermal unzipping reaction as well as the follow-updistillation step(s). The acid additives are necessary to preventpremature polymerization during workup and storage of thesecompositions. However, and as discussed above, as the chain lengthsbecome increasingly longer, higher temperatures are necessary to effectthe unzipping reaction. A direct unintended result is that excessivelevels of acid are necessary with the consequent overstabilization ofthe distilled product.

[0037] It, therefore, becomes necessary to negate this overstabilizationin order to facilitate the anionic polymerization. To date, all means ofeffecting this have been by pretreatment of the substrate with, forexample, alkaline and/or organic soluble amines that are intended toinitiate the anionic polymerization by dissolution into the adhesive.Though not specifically stated, this approach is apparently based on theview that as the mass of the side chain group increases, thepolymerizability drops off. This is apparent, as all current techniquesrely on overriding the excess stabilizer levels. Alternative methodsemploy a solution of these initiators being sprayed over the adhesiveafter it has been applied to the substrate. The other variant of thissoluble initiator method are those referenced above incorporating theinitiator in the porous applicator tip. As those skilled in the artcertainly appreciate, neither of these approaches is desirable formedical procedures.

[0038] With the foregoing in mind, a need currently exists for a methodby which cyanoacrylate adhesives may be rapidly cured withoutcontaminants or extraneous additive. The present invention provides sucha method.

SUMMARY OF THE INVENTION

[0039] It is, therefore, a principal object of the present invention toprovide a new and unobvious method for curing cyanoacrylate adhesives,permitting utilization of the resulting adhesives in the treatment ofhuman, or animal, tissue and/or flesh, required to be otherwise sealedor sutured, or otherwise protected from its surroundings. The method hasbeen developed so as to minimize the presence of contaminants andextraneous additives in the resulting cured medical adhesives.

[0040] It is further an object of the present invention to enhance thecure speed of stabilized cyanoacrylate adhesives by a treatment thatremoves excessive stabilizers prior to application onto the substrate.The present cyanoacrylate adhesives curing method allows for reducedlevels of stabilizers therein to be formulated to provide commerciallysufficient shelf life and improved speed of cure upon application. Thepresent method also enhances the cure speed of cyanoacrylate adhesivesby a destabilization treatment that purifies the cyanoacrylate prior tothe application onto the substrate and results in the production ofimproved cyanoacrylate adhesives that exhibit greater biocompatibilityas a consequence of modified polydispersity and longer monomeric chaingroups, especially such adhesives that exhibit attenuated degradation ofthe polymer thereby exposing tissue contacting the adhesive to lowerlevels of formaldehyde. The present cyanoacrylate adhesives curingmethod further allows for formulating unadulterated adhesives containingno plasticizers while achieving the elastomeric properties necessary forbonded substrates undergoing multidimensional stresses.

[0041] The objects are achieved by an adhesive method comprising thesteps of providing a long shelf life stable adhesive compositioncomprising cyanoacrylate adhesive and a stabilizing agent(s), presentinga substrate to receive at least a portion of the cyanoacrylate adhesivecomposition and applying the cyanoacrylate adhesive composition to thesubstrate. The method is further achieved by removing a predeterminedquantity excess stabilizing agent(s) from the cyanoacrylate adhesivecomposition prior to application to the substrate.

[0042] Other objects and further scope of applicability of the presentinvention will become apparent from the detailed descriptions givenherein; it should be understood, however, that the detaileddescriptions, while indicating preferred embodiments of the invention,are given by way of illustration only, since various changes andmodifications within the spirit and scope of the invention will becomeapparent to those skilled in the art from such descriptions.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0043] The detailed embodiments of the present invention are disclosedherein. It should be understood, however, that the disclosed embodimentsare merely exemplary of the invention, which may be embodied in variousforms. Therefore, the details disclosed herein are not to be interpretedas limited, but merely as the basis for the claims and as a basis forteaching one skilled in the art how to make and/or use the invention.

[0044] As discussed above, the present invention generally relates to amethod for curing reactive monomeric cyanoacrylates to undergomacromolecular formations via appropriate modification of anionicstabilizer levels in a manner permitting utilization of the resultingadhesives in the treatment of human, or animal, tissue and/or flesh,required to be otherwise sealed or sutured, or otherwise protected fromits surroundings. While certain distinctions may be drawn between theusage of the terms “flesh” and “tissue” within the scientific community,the terms are used herein interchangeably as referring to a generalsubstrate upon which those skilled in the art would understand thepresent adhesive to be utilized within the medical field for thetreatment of patients. Without being bound to a specific mechanism, suchmodification of the anionic stabilizer levels chemically and/orphysically removes stabilizing agents so the present method allows forreformulation of compositions capable of reasonable cure speeds withoutexternal anionic initiators.

[0045] The present method generally includes the steps of providing along shelf life stable adhesive composition comprising cyanoacrylateadhesive and a stabilizing agent(s), removing excess stabilizingagent(s) from the adhesive composition, presenting a substrate toreceive at least a portion of the cyanoacrylate adhesive composition andapplying the cyanoacrylate adhesive portion to the substrate.

[0046] Cyanoacrylate adhesives that may be used in accordance with thepresent invention, comprise one or more monomers having the followinggeneral structure:

CH2═C(CN)—C(O)—R

[0047] Without encumbering the body of this patent with specificexamples of moieties, reference is made to the numerous patentsdelineating the myriad of groups that can be represented by the moietydesignated as R, many representative examples being given in the citedreferences. With this in mind, these, as well as other moieties, may beemployed without departing from the spirit of the present invention. Inthe case of difunctional cyanoacrylates, R would be bound to tworeactive groups. These are, therefore, intended to define and beincluded by general reference to such prior art and by thoseknowledgeable thereof.

[0048] As discussed above in the Background of the Invention, thevarious methods for the synthesis of these monomers generally requirethe addition of acids and free radical inhibitors during the monomersynthesis. The free radical inhibitors prevent premature polymerizationduring the thermal unzipping reaction as well as the follow-updistillation step(s). The acid additives are necessary to preventpremature polymerization during work-up and storage of thesecompositions.

[0049] However, as the chain lengths become increasingly longer, highertemperatures are necessary to effect the unzipping reaction. A directunintended result is that excessive levels of acid are necessary withthe consequent overstabilization of the distilled product. It,therefore, becomes necessary to negate this overstabilization in orderto facilitate anionic polymerization of the adhesive composition.

[0050] Prior art techniques rely upon pretreatment of the substratewith, for example, alkaline and/or organic soluble amines that areintended to initiate the anionic polymerization by dissolution into theadhesive. This approach is apparently based on the view that as the massof the side chain group increases, the polymerizability drops off. Thisis apparent, as all current techniques rely on overriding the excessstabilizer levels. Alternative prior art methods employ a solution ofthese initiators being sprayed over the adhesive after it has beenapplied to the substrate. The other variant of this soluble initiatormethod are those referenced above incorporating the initiator in theporous applicator tip.

[0051] Since the difficulty in polymerization of these longer chainmoieties is due to excessive acid levels, in accordance with the presentinvention the acids are removed rather than neutralized. As noted above,polymerization is achieved by the addition of initiators to overcome thestabilizing effects of these acids and so remain in the resultantpolymer matrix. The concept of acid removal is also the focus of aco-pending U.S. patent application Ser. No. 09/982,226, filed Dec. 19,2001, which is incorporated herein by reference. The '226 applicationdescribes the use of acid removing particulates during the coincidentalapplication of these adhesives. The utility of this method is limited bya period of time in which the adhesive can be applied. It would be mostdesirable to have a greater degree of freedom in time to apply theseadhesives.

[0052] This present method achieves this goal by removing stabilizers incyanoacrylate adhesives prior to their application to substrates. Thisrenders the resultant purified compositions highly susceptible topolymerizations when applied to the substrates. Again, without beingbound to any single specific mechanism, this process relies on acombination of physical adsorption/absorption, chemical reaction, andhydrogen bonding of the acid group(s) onto particulate surfaces. It isnecessary to have the acid removing particulate substances, in fluidcontact with the excessively stabilized monomer(s), be insoluble orotherwise isolatable from the monomers, such as by filtration,centrifugation, phasing out, membrane separation, or other appropriateisolating mechanism. The requisite is the isolation of the acids orother stabilizers from the monomers.

[0053] Substances exhibiting these mechanisms encompass polymers capableof forming hydrogen bonds with the stabilizing acids. These polymericmaterials can have carbonyl, hydroxyl, amide, carboxylic, amine, ether,anhydride, ester, urethane, sulfone or other structures or combinationstructures capable of coupling or otherwise fixing the acid stabilizerto the isolatable substances. These polymeric materials can also beinorganic such as silicates. Other contemplated particulates are thosein which the stabilizers are selectively trapped in zeolytic substancesor otherwise caged in molecular sieves.

[0054] Chemical isolation can be achieved by, for example, reactivecontact with anhydride structures such as on copolymers containingmaleic anhydride. It is postulated that the anhydride structure reactsto form an anhydride link with the mobile (stabilizing) acid and acarboxylic group, both being bound to the polymer chain; an example forthis being maleic anhydride copolymers of styrene and ethylene.

[0055] Physical removal of the excess stabilizers may be accomplished bysuch substances as activated carbon, which appears to rely on adsorptionof the stabilizer(s) as a result of the high surface area and polarsurface structures.

[0056] These mechanisms of treatment are not meant to be mutuallyexclusive, but can, in fact, be acting by any and all combinations toremove the excessive stabilizers. A typical example is the use ofactivated carbon, which has oxidation structures that are likely toparticipate in hydrogen bonding as well as physical adsorption. Afurther example is the use of more than one substance, such aspolymer(s) and inorganic(s) in a single treatment.

[0057] To most effectively use stabilized cyanoacrylate adhesives formedical applications in accordance with the invention, they are storedin a device that houses a crushable ampoule containing such adhesives.Such ampoule containing devices may be constructed of any number ofmaterials that can be shaped or molded or otherwise fabricated tocontain the adhesive and ampoule. The application devices are preferablymanufactured from such materials as to effect a resilient wall capableof transmitting pressure to the crushable ampoule without loss of itscontainment properties. These application devices advantageously furthercomprise a filtering component and nozzle for application of thefiltered adhesive to the substrate, for example, tissue of the patientbeing treated. Examples of application devices which may be used inaccordance with the present method are disclosed in detail in the '226application which, as discussed above, is incorporated herein byreference.

[0058] The application devices can also be designed to apply the productin a continuous manner. An example of such a device is one thatincorporates a reservoir of the appropriate adhesive feeding through avalving mechanism, thereby providing a source of adhesive without anampoule.

[0059] In multi-application uses the properly treated cyanoacrylate iscontained in appropriate vessels such as glass or high densitypolyethylene. These containers may be pretreated so as to effect usefulshelf life. Reference again is made to those familiar with the art andpatents delineating the various methods to achieve this treatment.Typically a container would hold 2-5 grams of product to provide manytopical applications with appropriate disposable applicators such aspipettes.

[0060] In a preferred embodiment, one of the above described deviceshouses iso-octyl cyanoacrylate which has been previously treated withpoly(vinyl pyrrolidone/vinyl acetate) copolymer. The ampoule is crushedand the contents are then expressed through the appropriate filter anddispenser tip onto the substrate, specifically human, or animal tissue,or skin. The application is accomplished in such fashion as to preventencapsulation of adhesive by any surrounding tissue. Though ultimatelythese inclusions are degraded and excreted, it is most desirable tominimize this occurrence to maximize reconstitution of the surroundingtissue. The need to assure this minimization was noted in U.S. Pat. No.3,667,472 which pointed out the requisite to bridge the wound withoutdiffusing into it. This was accomplished by bringing the wound edgestogether followed by application so as to effect a bridging over thewound to circumvent necrosis and irritation by this technique.

[0061] A second preferred embodiment utilizes the above describeddevices containing iso-decyl cyanoacrylate

[0062] A third preferred embodiment utilizes the above described devicescontaining dodecyl cyanoacrylate.

[0063] A fourth preferred embodiment includes the above withcombinations of cyanoacrylate monomers to achieve control over the rateof hydrolytic degradation so as to improve compatibility with tissue bycontrol of formaldehyde emissions.

[0064] In accordance with a preferred embodiment, the invention employsvinyl pyrrolidone polymers and copolymers to remove stabilizers from thecyanoacrylate adhesives formulation. These particulate agents arecombined with the monomer adhesive in mutual contact until the adhesiveis destabilized, whereupon the adhesive becomes isolated from thedestabilizing agent by various means such as to effect isolation of theadhesive from the destabilizing component. Once isolated, the adhesiveis restabilized at reduced levels so as to effect timely cure rates inthe 5 seconds to approximately one minute range.

[0065] Advantageously, the device of the invention is one that (a)delivers the cyanoacrylate adhesive of convenient viscosity, (b)contains a porous segment for the containment of the ampoule and othercomponents so as to permit the release of the adhesive with noparticulate components being released onto the substrate to which it isapplied, (c) delivers the adhesive through a nozzle applicator tipconfigured for appropriate application onto the substrate, and (d) canbe used with other monomer formulations prior to application to effectthe desired result such as polymerizations to produce variousthermoplastic and thermoset resins of both organic and inorganic nature.

[0066] All of preferred embodiments disclosed in accordance with thepresent invention should be understood to further include all of thevarious additives useful in the alteration and improvement tocyanoacrylate adhesives as would make them suitable for placement intothe above devices and modifications to these and similar devices. Thesecan include plasticizers, stabilizers, surface insensitive additives,tougheners, thickeners, adhesion promoters, other monomers, comonomers,and other such compositions as would be evident to those familiar withthe cyanoacrylate adhesives art.

[0067] The following preferred examples further disclose the new methodand display its effectiveness.

EXAMPLE 1

[0068] A quantity of particulate destabilizing agent (5 grams) in theform of vinyl pyrrolidone vinyl acetate copolymer is blended with (25grams) iso-octyl cyanoacrylate for a period of 24 hours. The resultantslurry is filtered to effectively remove the destabilizing agent and isrestabilized at a level to achieve the desired cure speed for thefollowing test. In particular, 6 grams of the treated monomer is blendedwith 0.012 grams of pretreated monomer. A glass ampoule is charged with0.5 grams of treated monomer and sealed with a gas flame. The ampoule isinserted into a tubular device referred to as a Tandem Dropper suppliedby James Alexander Company of Blairstown, N.J., that also providedunsealed ampoules. In order to filter matter dispensed from thedispenser tip of the Tandem Dropper, it is plugged internally with asmall wad of polyester fiber also supplied by James Alexander Company.The dispenser tip press fits onto the end of the Tandem Dropper afterinsertion of the sealed ampoule. The assembled device is squeezed toeffect rupture of the ampoule. Pressure is applied so as to exude a dropof adhesive through the filtering tip. The drop is applied to skin andtimed to determine when the film has undergone cure to a non-tackysurface. The iso-octyl cyanoacrylate undergoes cure in 10-20 secondsupon application to skin on the back of the hand. This contrasts withuntreated iso-octyl cyanaocrylate which shows no sign of cure up to 3minutes whereupon the test is terminated.

EXAMPLE 2

[0069] A 10 milliliter glass vial is charged with 0.5 grams of activatedcharcoal Calgon WPX, sourced from Calgon Carbon Corp. of Pittsburgh Pa.Followed by this is a 6.0 gram charge of iso-octyl cyanoacrylate whichis mixed for a period of 30 minutes. The resulting dispersion isfiltered to isolate the cyanoacrylate into a small ampoule. A test ofcure speed on skin of the isolated monomer results in the formation of aprotective film in 10 to 20 seconds in a manner similar to example 1above.

EXAMPLE 3

[0070] A 3 milliliter test tube is charged with 0.016 grams of anhydrouspotassium carbonate and 2.030 grams of iso-octyl cyanoacrylate which isthen sealed and shaken for approximately 2 hours. It is stored for 17days. A sample is removed and applied to the skin with a consequent filmcure in a range of 110 to 120 seconds.

EXAMPLE 4

[0071] Example 3 is repeated with a higher loading of the anhydrouscarbonate: 0.27 grams and 2.46 grams of iso-octyl cyanoacrylate. Thetest tube is stored for 15 days whereupon a test of cure exhibits filmformation in 120 seconds.

EXAMPLE 5

[0072] A 50 milliliter flask is charged and sealed with 1.5 grams ofpolyvinyl alcohol granules (BP-05) and 18.5 grams of iso-octylcyanoacrylate. The dispersion is intermittently shaken for a period of48 hours due to the more coarse nature of the polymer. A sample is takenand tested on skin to show a cure of film in 90 to 100 seconds.

EXAMPLE 6

[0073] A flask is charged and sealed with 1.0 grams of ethylene-vinylacetate copolymer RP251 (Wacker Polysystems) and 18.5 grams of iso-octylcyanaocrylate. The dispersion is intermittently shaken for 48 hoursprior to the skin test. Upon testing the treated monomer cured inapproximately 100 seconds

EXAMPLE 7

[0074] Example 6 is repeated with RP140, a vinyl acetate homopolymer.The resultant treated monomer gave a cure after 130 seconds.

EXAMPLE 8

[0075] A 10 milliliter flask is charged and sealed with 1.0 grams ofpoly(methyl methacrylate) (Rhohadon M449, Rohmtech Inc.) and 6 grams ofiso-octyl cyanaocrylate After intermittent shaking for 24 hours, thedispersion is filtered and the isolated monomer is tested to reveal afilm formation in 30 to 35 seconds.

EXAMPLE 9

[0076] A 10 milliliter flask is charged and sealed with 1.0 grams ofstyrene-maleic anhydride copolymer (SMA-3000, Atochem Inc.) and 6 gramsof iso-octyl cyanoacrylate. Subsequent isolation of the monomer after 24hours of treatment gave a cured film on skin in approximately 65seconds.

EXAMPLE 10

[0077] A 10 milliliter flask is charged and sealed with 0.5 grams ofzinc oxide (AZO66, US Zinc Products Inc.) and 6 grams of iso-octylcyanoacrylate After shaking the dispersion for 30 minutes, subsequentfiltration and testing on skin gave a cure in 50 to 60 seconds.

EXAMPLE 11

[0078] A 10 milliliter flask is charged and sealed with 0.5 grams of“Hydrosource” (12 mm average diameter particles) polyacrylamide (CastleInternational) and 6.0 grams of iso-octyl cyanoacrylate. Subsequenttesting after 4 hours of mixing gave a 30 second cure on skin.

EXAMPLE 12

[0079] A 10 milliliter flask is charged and sealed with 1.6 grams ofglass spheres (Class 4A size 203 from Cataphote Corp.) and 4.4 grams ofiso-octyl cyanoacrylate. The mix was shaken for 2 hours prior totesting. The sampled droplet was spread on skin giving a 60 second cure.

EXAMPLE 13

[0080] A 10 milliliter flask is charged and sealed with 1.6 grams ofpulverized polyimide resin (Dupont Kapton 700HPP-ST film) and 4.4 gramsof iso-octyl cyanoacrylate. The mix was shaken overnight prior totesting. An isolated sample gave a skin surface cure of 120 seconds.

EXAMPLE 14

[0081] A two ounce opaque polyethylene bottle is charged with 0.57 gramsof vinyl pyrrolidone vinyl acetate copolymer and 30 grams of iso-octylcyanoacrylate. The container is shaken for five minutes and stored for 3months. A sample was taken and passed through a 0.2 micron filter with a1 milliliter syringe. Application onto skin gave a very rapid cure of10-15 seconds with a noticeable warmth due to the more rapidpolymerization.

[0082] As evidenced by the last example, these additives can be left incontact with the cyanoacrylate with no apparent detriment to the shelflife and cure of the final product. It is further evident that theseproducts can be kept without the need to isolate and store in glassampoules. This further leads to the capability of large reservoirs ofproduct to be dispensable through a disposable fibrous or porous tip.This is particularly advantageous in procedures where quantitiesnecessary exceed the capacity of the crushable ampoules. The onlylimitations to the various treatments is the ability to isolate apractical level of cyanoacrylate monomer, i.e., that concentrations evenat levels creating slurries can be filtered off to achieve economicquantities. These examples serve to show the extensive applicability ofthe primary requisite: to remove excessive stabilizer(s). No otherreferences have addressed this issue, as those knowledgeable in thescience and art of this technology have always understood the need toadd, not remove, these stabilizing substances. It has not previouslybeen recognized that the synthesis and isolation of these long chainside group cyanoacrylates results in excessive levels of thesestabilizers. The preceding examples are intended to show the varioustypes of cyanoacrylate insoluble materials that can perform theextraction of stabilizers. They are therefore intended to exemplify, notdefine the limits, of applicable substances.

[0083] While the preferred embodiments have been shown and described, itwill be understood that there is no intent to limit the invention bysuch disclosure, but rather, is intended to cover all modifications andalternate constructions falling within the spirit and scope of theinvention as defined in the appended claims.

I claim:
 1. A method for the fabrication of a cyanoacrylate adhesive soas to minimize the presence of contaminants and extraneous additives inthe resulting cured adhesives and enhancing the cure speed of stabilizedcyanoacrylate adhesive by a treatment that removes excessive stabilizersprior to application onto a substrate, the method comprising the stepsof (a) providing a stable adhesive composition comprising cyanoacrylateadhesive and a stabilizing agent to produce a cyanoacrylate adhesivecomposition, (b) presenting a substrate to receive at least a portion ofthe cyanoacrylate adhesive composition and (c) applying thecyanoacrylate adhesive composition to the substrate, the improvementcomprising the step of removing stabilizing agent from the cyanoacrylateadhesive composition prior to the step of applying.
 2. The methodaccording to claim 1, wherein the cyanoacrylate adhesive comprises oneor more monomers having the general structure. CH2═C(CN)—C(O)—R.
 3. Themethod according to claim 2, wherein “R” is selected from the groupconsisting of octyl, decyl, dodecyl, and tridecyl.
 4. The methodaccording to claim 2, wherein the cyanoacrylate adhesive comprises adifunctional cyanoacrylate.
 5. The method according to claim 1, whereinthe step of removing stabilizing agent from the cyanoacrylate adhesivecomposition comprises contacting the cyanoacrylate composition with aparticulate agent.
 6. The method according to claim 5, wherein theparticulate agent is selected from the group consisting of vinylpyrrolidone and copolymers of pyrrolidone.
 7. The method according toclaim 5, wherein the particulate agent is selected from the groupconsisting of polymeric materials having carbonyl, hydroxyl, amide,carboxylic, amine, ether, anhydride, ester, urethane or sulfonestructures, silicates anhydride structures and activated carbon.
 8. Themethod according to claim 1, wherein the substrate is tissue required tobe sutured or sealed, or otherwise protected from its surroundings. 9.The method according to claim 1, wherein the step of removing excessstabilizing agent is chosen from the group of mechanisms consisting ofphysical adsorption/absorption, chemical reaction, and hydrogen bondingof acid groups.
 10. A method for the fabrication of a cyanoacrylateadhesive so as to minimize the presence of contaminants and extraneousadditives in the resulting cured adhesives and enhancing the cure speedof stabilized cyanoacrylate adhesive by a treatment that removesexcessive stabilizers prior to application onto a substrate, the methodcomprising the following steps: providing stable adhesive compositioncomprising cyanoacrylate adhesive and a stabilizing agent to produce acyanoacrylate adhesive composition; removing stabilizing agent from thecyanoacrylate adhesive composition; presenting a substrate to receive atleast a portion of the cyanoacrylate adhesive composition; and applyingthe cyanoacrylate adhesive composition to the substrate.
 11. The methodaccording to claim 10, wherein the cyanoacrylate adhesive comprises oneor more monomers having the general structure. CH2═C(CN)—C(O)—R.
 12. Themethod according to claim 11, wherein “R” is selected from the groupconsisting of octyl, decyl, dodecyl, and tridecyl.
 13. The methodaccording to claim 11, wherein the cyanoacrylate adhesive comprises adifunctional cyanoacrylate.
 14. The method according to claim 10,wherein the step of removing stabilizing agent from the cyanoacrylateadhesive composition comprises contacting the cyanoacrylate compositionwith a particulate agent.
 15. The method according to claim 14, whereinthe particulate agent is selected from the group consisting of vinylpyrrolidone and copolymers of pyrrolidone.
 16. The method according toclaim 14, wherein the particulate agent is selected from the groupconsisting of polymeric materials having carbonyl, hydroxyl, amide,carboxylic, amine, ether, anhydride, ester, urethane or sulfonestructures, silicates anhydride structures and activated carbon.
 17. Themethod according to claim 10, wherein the substrate is tissue requiredto be sutured or sealed, or otherwise protected from its surroundings.18. The method according to claim 10, wherein the step of removingexcess stabilizing agent is chosen from the group of mechanismsconsisting of physical adsorption/absorption, chemical reaction, andhydrogen bonding of acid groups.